Substituted 2, 7-dioxaspiro(4.4)nonanes



United States Patent 3,275,660 r SUBSTITUTED 2,7-DIOXASPIRO(4.4)NONANESBurton Kendall Wasson, 103 Broadview Ave., Valois, Quebec, Canada, andJohn Mulvin Parker, 480 Three Valley Crescent, London, Ontario, CanadaNo Drawing. Filed Dec. 2, 1965, Ser; No. 511,212 7 Claims. (Cl.260-347.7)

ture

ou :-o

D -C HaR wherein R represents di(lower alkyl) amino; di(loweralky1)amino (lower alkyl)amino; Y-phenyl(=lower alkyl)- amino, wherein Ymay be bromo, methyl, ethyl, methoxy, ethoxy; ortho, meta andparapyridyl (lower alkyl)- amino; bicyclo(2: 2: 1 -5-hepten-2-yl(l-oweralkyl) amino; pyrrolidinyl; piperidinyl; morph0linyl; imid-azolyl; and

. halo.

The new 3,3-dimethy1-8-(substituted,methyl)-2,7-dioxaspi-ro(4.4)-nonanes are conveniently prepared byheating the appropriate primary or secondary amine with 3,3- dimethyl 8bromomethyl 2,7 di0xaspiro(4.4) n0- nane, with purification of the freebase by distillation, or by conversion to a salt followed bycrystallization. In each case, excess amine was used to-serve as-a--so1- vent for the reaction mixture. The reaction tempera ture may bevaried from 115 to 160 C. The acid addition salts may be converted tothe free base by treatment with alkali or metal carbonates followed bydistillation in vacuo.

Furthermore, 3,3 dimethyl-8-bromomethyl-2,7-dioxa- -spiro(4.4)-nonanewas the major'product when 2-methdiethyl ether to give2,2-dirnethy1-4(2,3-dibromopr0pyl)- 4-hydroxymethyltetrahydrofuran,followed by ring clos me using quinoline to remove the elements ofhydrogen bromide.

Suitable variables are illustrated by the following typical examples:

3,3-dimethyl-8-bromomethyl-2,7-dioxaspiro (4.4)nonane3,3-d1imethyl-8-dibntylaminomethyl-2,7-dioxaspiro(4.4)-

nonane hydrochloride T3,3-dimethyl-8-dimethylaminQmethyI-Z,7-dioxaspiro(4.4)-

nonane 3,3-dimethyl-8-diethylaaminomethyl-2,7-dioxaspiro(4.4)-

nonane 3,3-dimethyl-8-dipropylaminomethyl-2,7-dioxaspiro (4.4)

, nonane 3,3-dimethyil-S-diisopropylaminomethyl-2,7-dioxaspiri- (4.4)nonane 3,275,660 Patented Sept. 27, 1966 ICC3,3-dimethyl-8-disecbutylaminomethyl-2,7-dioxaspiro- (4.4)nonane3,3-dimethyl-8.-ditertbutylaminomethyl-2,7-dioxaspiro- (4.4)nonane e 3,3-dimethyl-8-diamylaminomethyl-Z,7-dioxaspiro (4.4

nonane I 3,3dimethyl-8-dihexylaminomethy1-2,7-dioxaspiro(4.4)-

nonane 3,3-dimethyl-8- 3 -diethylaminopropylaminomethyl) -2,7-

dioxa:spiro(4.4)nonane 3 ,3-dimethyl-8- 3-diethylaminopropylaminomethyl) -2,7-

dioxaspiro (4.4)nonan-e dihydrobrornide3,3-dimethyl-8-(N,N-dimethylaminomethyl-aminovmethyl)-2,7-dioxaspiro(4.4)nonane 13,3-dimethyl-8-(N,N-diethylaminomethylaminomethyl)-2,7-dioxaspiro(4.4)nonane 3,3-dimethy1-8-(N,N-dipropylaminomethylaminomethyl)2,7-dioxaspi-ro(4.4)nonane V3,3-dimethyl-8-(Z-dimethylaminoethylaminomethyl)-2,7-dioxaspiro(4.4)nonane i 3 ,3 -dimethyl-8-(2-diethylaminoethylaminomethyl -2,7-

dioxaspiro(4.4)nonane 3 ,3-dimethyl-8- 2-dipropylaminoethylaminomethyl-2,7- dioxaspiro(4.4)nonane 3 ,3-dimethyl-8-3-dimethylarninopropylaminomethyl) 2,7-dioxaspiro (4.4) nonane 3,3-dimethyl-8- 3-dipropylaminopropylaminomethyl) 2,7-dioxaspiro (4.4)nonane 3 ,3-dimethyl-8- 2-(p-chlorophenylethyl)aminomethyl)2,7-dioxaspiro(4.4)nonane 3,3-dirnethyl-8(2=(p-chlorophenylethyl)-amitiomethyl)- 2,7-dioxaspiro(4.4)nonanehydrochloride 3,3-dimethyl-8-(0-, m-, orp-chlorophenylalkylaminomethyl)-2,7-dioxaspiro(4.4)nonane 3,3-dimethyl-8-(m-pyridylmethyl-aminomethyl) -2,7-dioxaspi-ro( 4.4)nonane3 ,3 -dimethyl-8- (m-pyridylmethylaminomethyl) -2,-7- dioxaspiro- 4.4)nonane dihydrochloride:

3 3 -dimethyl-8- o-pynidylmethylaminomethyl) -2,7-di0xaspiro(4.4)no nane3,3-dimethyl-8- (p-pyridylmethylaminomethyl) -2,7-di0xaspire-(4.4)nonane3,3 -dimethy1-8- o-pyridylaminomethyl) -2,7-dioxaspiro- (4.4) nonane 3,3-dimethyl-8- (m-pyridylaminomethyl) -2,7-dioxa-spiro- (4.4)nonane 3 ,3-dimethyl-8- p-pynidylaminomethyl) -2,7 -dioxaspiro- (4.4)nonane 3 ,3-dimethyl-8- (2-opyridylethylaminornethyl) -2,7-dioxaspiro 4.4) nonane 3,3-dimethyl-8- 2-m-pyridylethylaminomethyl) 2,7-dioxaspiro (4.4) nonane3,3-dimethyl-8- (2-p-pyridylethylaminomethyl) -2,7-dioxaspiro 4.4)nonane 3 ,3 dimethyl-8-(2-bicyc1o (2: 2 1 )-5-heptenyl-methylaminomethyl-2,7-diox-aspiro 4.4) nonane 3,3-dimethy1-8- 2-bicyclo( 2 2:1)-5-heptenylmethylaminomethyl) -2,7-dioxaspiro(4.4) nonanehydrochloride 3 3-dimethyl-8- (N-pyrrolidinylmethyl) -2,7-dioxaspi-ro-(nona e t 3 ,3-dimethyl-8- (N-pyrrolidinylmethyl-Z,7 dioxa spiro-(4.4)non:ane hydrochloride 3 3 -dimethy1-8- (N-piperidylmethyl)-2,7-dioxaspiro (4.4)

nonane 3 ,3 dimethyl-8-morpholinylmethy1-2,7-dioxaspiro(4.4)

nonane 3,3-dimethyl-8- (N-morpholinylrnethyl) -2,7-dioxaspiro-(4.4)nonane hydrochloride 3,3-dlmethyl-8-(N-rnorpholinylrnethylaminomethyl -2,7-

dioxaspiro (4.4) nonane 3 3,3-dimethyl-8-(2-(N-morpholinylethyl)-aminomethyl)-2,7-dioxaspiro(4.4)nonane 3,3-dimethyl-8- 3-(N-morpholinylpropyl)aminomethyl) 2,7-dioxaspiro(4.4)nonane 3,3-dimethyl-8-1-imidazolylmethyl) 2,7-dioxaspiro (4.4)

nonane The compounds to which this invention relates are'useful becauseof their valuable pharmacological properties.

Thus, for example, 3,3-dimethyl-8-bromomethyl-2,7-dioxaspiro(4.4)nonane, 3,3-dimethyl- 8(3-diethylaminopropylarninomethyl)-2,7-dioxaspiro(4.4)nonanedihydrobromide and3,3-dimethyl-8-'(2-bicyclo(2:2:11)-5-heptenylmethylam-inomethyl) 2,7dioxaspiro (4.4)nonane hydro- 4 was heated and stirred for 3 hours at110420 C. The

cooled reaction mixture was treated with 1.6 grams of chloride exhibitsedative properties when tested on a strain of laboratory rats, as seenby gross observation. Some of them, forexample: I

3,3 -dimethyl-8 bromomethyl-2,7-dioxaspiro (4.4) nonane 3,3 1d-imethyl-8-(3-diethylaminopropylaminomethyl)-2,7-

dioxaspiro( 4.4) nonane dihydrobromide -3,3 dimethyl 8 (2-bicyclo(2:2:1)5 heptenylmethylare capable of blocking or depressing thepsychotomimetic effects of p-chlorophenylethylamine (an analogue ofmescaline) and mescaline.

The preparations of the present invention will be more fully understoodby referring to the following examples:

EXAMPLE I 3,3-dimethyl-8-bromomethyl-2,7-di0xaspiro(4.4)nonane 2,2dimethyl-4-a1lyl-4-hydroxymethyltetrahydrofuran (76.5 grams) in 450 ml.of anhydrous ethyl ether was cooled to C. Then 72 grams of bromine wasadded dropwise during a period of 75 minutes. The mixture was stirred afurther 'minutes. Quinoline (58.2 grams) dissolved in 150 ml. ofanhydrous ether was added during a period of 25 minute-s whilemaintaining the internal temperature at -25 C. The solid was collected,tritu'rated several times with ether, the combined ethereal extractswashed with 3 N hydrochloric acid, water and evaporated. The residue wasdistilled at 95-137" C./ 10 mm. to give 60.9 grams of3,3-di'methyl-8bromomethy1- 2,7-dioxaspiro (4.4)nonane, n 1.4882.Redistillation of this product through a spinning band afforded an"EXAMPLE n 3,3-dimethyl-8-dibutylaminomethyl-2,7- dioxaspir0*(4.4 nonaneou 0 /C H o onm sodium hydroxide in 16 ml. of Water and extracted withether. The extract was concentrated .and the 10.8 grams of crude productwas converted into the hydrochloride salt. Recrystallization of thissalt from ethyl acetate and ligroi-ne gave 3,3 dimethyl 8dibutylarninomet-hyl-2,7- dioxaspiro(4.4)nonane hydrochloride having aM.P. of 112-114 C. This salt was hydroscopic and an analytical sample ofthe free base was obtained as follows. The salt was dissolved in water,the solution made basic, extracted with ether, and distilled to givepure 3,3-dimethyl- 8-dibutylaminomethyl-ZJ-dioxaspiro(4.4)nonane boilingat 9697 C./0.05 mm, n .1.4588.

Analysis.Calculated for C H NO C: 72.67%, H: 11.86%, N: 4.71%. Found: C:72.88%, H: 11.74%,

Infrared analysis showed the disappearance of the hromo groups.

Similarly, condensation of 3,3-dimethyl-8-'bromornethyl-2,7-dioxaspiro(4.4)nonane with dimethylamine, di'ethylamine,dipropylamine, diisopropylamine, disecondary- ,buty-larnine,.ditertiarybutylamine, diamylamine and dihexylamine would give3,3-dimethyl-8-dimethylaminomethyl-2,7-dioxaspiro(4.4)nonane,3,3-dimethy1-8diethylaminomethyl-2,7dioxaspiro(4.4)nonane,3,3-dimethyl-8- dipropylaminomethyl-Z,7-dioxaspiro(4.4) nonane,3,3-dimethyl 8 diisopropylaminomethyl 2,7 dioxaspiro (4.4)nonane,3,3-dirnethyl-8-disec. butylaminomethyl-2,7- dioxaspiro(4.4)nonane,3,3-dimethyl-S diterLhutylaminomethyl-2,7-dioxaspiro(4.4) nonane,3,3-dimethy1-8-diamylaminomethyl-2,7dioxaspiro (4.4)nonane, and3,3-dimethy-S-dihexylaminomethyl-2,7 dioxaspiro(4.4)nonane respectively.

' EXAMPLE III 3,3-dimethyl-8-(3-diethylamin0pr0pylaminomethyl)-2,7-dioxaspiro (4 .4 )nonane to remove the unchanged3,3-dimethy1-8bromomethyl- 2,7-dioxaspir o(4.4)nonane. The aqueous layerwas made basicwith dilute sodium hydroxide and extracted with ether. Thecombined ethereal extracts were washed with water and evaporated to give23.3 grams of residue. Distillation of this residue afforded 20.5 gramsof 3,3-dimethyl 8 (3 diethylaminopropylaminomethyl-2,7-di--oxaspiro(4.4)n'onane boiling at 1401-82 C./ 6 mm. This material wasredistilled using a spinning band column to give relatively pure3,3-dimethyl-8-(3-diethy1arrrinopropylaminomethyl)-2,7-dioxaspiro(4.4)nonaneboiling at 158-160 C./6 mm. Treatment of the free base with-=hydrobromic acid alforded an analytical sample of 3,3-

A solution of 10 grams of 3,3-dimethyl-8-bromomethyl-2,7-dioxaspi-ro(4.4) nonane and 20 grams of dib-utylamine dimethyl 8 (3diethylam-inopropylaminornethyl) -2,7- dioxaspiro(4.4)nonanedihydrobromide having a melt-ing point of 98-101 C. when recrystallizedfrom anhydrous acetone.

Analysis-Calculated for C H O N QHBr; C: 44.34%, H: 8.01%, N: 5.95%.Found: C: 44.35%, H: 7.88%, N: 6.09%. I

Similarly, condensation of 3,3-dimethyl-8-bromomethy'l 2,7-dioxaspiro(4.4) nonane-with. the appropriate dialkyldiethylaminomethylaminomethyl)2,7 di-oxaspiro (4.4)- nonane,3,3-dimethyl-8-(N,N-dipropylaminomethylaminomethyl) -2,7-dioxaspiro(4.4) nonane, 3,3-dimethyl-8- (2-dimethylaminoethylaminomethyl)2,7-dioxaspiro(4.4)nonane,3,3-dimethyl-8-(2-diethylaminoethylaminomethyl)- 2,7dioxaspiro(4.4)nonane, 3,3-dimethyl-8-(Z-dipropylaminoethylaminomethyl-2,7-dioxaspiro- (4.4 nonane, 3 ,3- dimethyl 8-(3dimethylaminopropylaminomethyl)-2,7- dioxaspiro(4.4)nonane,3,3dimethyl-8-(3-dipropylaminopropylaminomethyl) -2,7-dioxaspir-o (4.4nonane, and their acid addition salts.

EXAMPLE IV 3,3-dimethyl-8-(2-(pwhlo'rophenylethyl)amin0methyl)-2,7-di0xaspir0(4.4)nonane In the same manner as set forth in ExampleIII, a mixture of 20 grams of3,3-dimethyl-8-bromo-methy1-2,7-dioxaspiro(4.4)nonane and 37.4 grams ofp-chlorophenethylamine was heated 4 hours at 125-150 C. and the productwas distilled under reduced pressure to give 18.3 grams of3,3-dimethyl-8-(2-(p-chlorophenylethyl)aminoethyl)-2,7-dioxaspiro(4.4)nonaneas a colourless oil boiling at 140-155/0.05 mm., n 1.5240. A solution ofthe free base in concentrated hydrochloric acid was evaporated in vacuo,and the residue dried by repeated evaporation from a solution of benzeneand alcohol. The resulting 3,3dimethyl-8-(Z-(p-chlorophenylethyl)-arninomethyl)-2,7-dioxaspiro(4.4)nonane hydrochloride was recrystallized from methanol and ethylether melting at 220 C. (decomposition).

Analysis.Calculated for 60.00%; H, 8.09%; N, 3.89%. 8.25%; N, 3.92%.

Similarly, condensation of3,3-dimethyl-8-bromomethyl-2,7-dioxaspiro(4.4)nonane with theappropriate 0-, mor p-(aminoalkylphenyl) chloride gives thecorresponding 3,3-dimethy1-8-(o-, m orp-chlorophenylalkylaminomethyl)-2,7-dioxaspiro(4.4)nonane wherein thealkyl group may contain from one to six carbon atoms. Condensations maybe carried out with amines of the general formula mQ-wrmmm wherein Rrepresents a group, o-, mor p-, such as bromide, methyl, ethyl, methoxy,ethoxy, etc. and 11 consists of whole numbers from one to six. The acidaddition salts of the above products may be considered as a part of thisinvention.

CmHgoClNOg C, Found: C, 60.08%; H,

EXAMPLE V 3,3-dimethyl-8-(m-pyridylmethylam inomethyl) -2,7-

dioxaspir0(4.4) nonane D CHaNHCH2 6 dimethyl 8(m-pyridylrnethylaminomethyl)2,7-dioxaspir0(4.4)nonane boiling at141.5-143..0/0.05 mm., 11 1.5183.

Analysis.Calculated for C H N 0 C, 69.53%; H, 8.75%; N, 10.14%. Found:C, 69.60%; H, 8.77%; N, 10.39%.

Similarly, condensation of3,3-dimethyl-8-bromo-methyl-2,7-dioxaspir-o(4.4)nonane with theappropriate o-, m-

and p-(aminoalkyl)pyridine gives the following com- EXAMPLE VI3,3-dimethyl-8-(2-bicyclo(2:2 :1 -5-hep tenylmelhylaminomethyl-2,7-dioxaspiro (4 .4 nonane In the same manner as set forth in ExampleIII, a mixture of 20 grams of3,3-dimethyl-8-brom-omethyl-2,7-dioxaspiro(4.4)n-onane and 29.7 grams of2-aminomethylbicyclo(2:2:1)-5-heptene was heated 3 hours at C. The crudeproduct was distilled to give 3,3-dimethyl-8-(2- bicyclo(2:2:1) 5heptenylmethylaminornethyl)-2,7-dioxaspiro(4.4)nonane boiling at 134142C./0.05 mm., n 1.4951. Treatment of the free base withdilute'hydrochloric acid gave an analytical sample of 3,3-dimethyl- 8(2-bicyclo(2:2:1)-5-heptenylmethylaminomethyl)2,7- dioxaspiro(4.4)nonanehydrochloride melting at 193- 195 C.

Analysis.Calculated for C H NO -HCl: C, 65.93%; H, 9.22%; N, 4.27%.Found: C, 66.14%; H, 8.91%; N, 4.26%.

EXAMPLE VII 3,3-dimethyl-8-(N-pyrrolidinylmetlzyl) -2,7- dioxaspiro (4.4 nonaine In the same manner as set forth in Example III, a mixture of3,3-dimethy1-8-bromo'methyl-2,7-dioxaspiro(4.4)- nonane and pyrrolidinewas refluxed for a period of 2 hours. The excess pyrrolidine was removedby distillation in vacuo. The residue was treated with dilutehydrochloric acid, and the product was recrystallized from acetone-ethylether to give pure 3,3-dimethyl-8-(N-pyrrolidinylmethyl)2,7-dioxaspiro(4.4)nonane hydrochloride melting at 169.5-170.5 C.

Analysis.-Calculated for C H NO .HCl: C, 60.96%; H, 9.50%; N, 5.08%.Found: C, 61.28%; H, 9.50%; N, 4.97%.

7 EXAMPLE VIII DCLCHH In the same manner as set forth in Example III, amixture of 15.9 grams of 3,3-dimethyl-8-bromomethyl-2,7-dioxaspiro(4.4)nonane and 15.3 grams of piperidine was heated one hourat 135 C. The crude product was distilled at 94110 C./ 0.04 mm. to give13.0 grams of 3,3- dimethyl 8(N-piperidylmethyl)-2,7-dioxaspiro(4.4)noname. The hydrochloride saltwas prepared, melting at 168-,170 C. An analytical sample of3,3-dimethyl-8- (N-piperidylmethyl)-2,7-dioxaspiro(4.4)nonane wasobtained by neutralizing the recrystallized hydrochloride and distillingthe free base through a spinning band column boiling at 82 C./0.05 mm.,n 1.4805.

Analysis.Calculated for C H NO C, 71.10%; H, 10.74%; N, 5.53%. Found: C,71.13%; H, 10.32%; N, 5.46%. 2

EXAMPLE IX 3,3-aimethyl-8-m0rpholinylmethyl-2,7-dioxaspir0 (4 .4

nonane In the same manner as set forth in Example III a mixture of gramsof 3,3-dimethyl-8-bromomethyl-2,7- diox-aspiro(4.4)nona ne and 21 gramsof morphol-ine was heated 4 hours at 120-125 C. The product wasdistilled to give 13.5 grams of 3,3-dimethyl-8-morpholinylmethyl- I2,7-dioxaspiro(4.4)monane boiling at 115136.5 C./0.05

mm., n 1.4801. The free base was treated with hydrochloric acid and theproduct crystallized to give 3,3-dimethylS-(N-morpholinylmethyl)-2,7-dioxaspiro(4.4)-

nonane hydrochloride melting at 158-162 C.

3,3-dim ethyl-8- (1 -imidaz0lylmethyl) -2,7-dioxaspir0- (4.4 nonane Inthe same manner as set forth in Example 'III,a mixture of 20 grams of3,3-dimethyl-8-bromomethyl-2,7-dioxaspiro(4.4)nonane and 10.9 grams ofimidazole was heated 4hours at -135 C. The crude product was distilledto give pure 3,3-dimethyl-8-(1-imidazolylmethy1)-2,7-dioxaspiro(4.4)nonane boiling at 132 C./0.05 mm., 11 1.5031. Thehyrochloride salt was prepared in the customary manner melting at 153158C.

Analysis.-Ca1culated for C H N O C: 66.07%, H: 8.53%, N: 11.86%. Found:C: 66.19%, H: 8.63%, N: 11.46%.

All of the compounds of the present invention which have an amino groupare useful as curing agents for urea formaldehyde and melamineformaldehyde resins. The amino group can be either an aliphatic aminogroup or a heterocycli-c amino group. The compounds of the presentinvention which are not in the form of a free base can be converted intotheir hydrochloride salt, and in such form are also useful as curingagents for melamine formaldehyde and urea formaldehyde resins. Thus, anyof the compounds of Examples II through X are useful as curing agentsfor melamine formaldehyde resins.

We claim:

1. A compound of the formula:

DCI

O CH2R and non-toxic acid addition salts thereof wherein R is a memberof the group consisting of (1) Y-phenyl(lower alkyl)amino where Y is amember of the group consisting of bromo, methyl, ethyl, methoxy andethoxy, and (2) bicyclo( 2 2: 1 )-5-hepten-2-yl(lower alkyl) amino.

2. A compound of claim 1 which is 3,3-dimcthyl-8- (2 (pchlorophenylethyl) -aminomethyl) -2,7-dioxaspiro- (4.4)nonanehydrochloride.

3. A compound of claim 1 which is 3,3-dimethyl-8- (orthochlorophenylalkylaminomethyl)-2,7-dioxaspiro- (4.4)nonane.

4. A compound of claim 1 which is 3,3,-dimethyl-8 (metachlorophenylalkylaminomethyl)-2,8-dioxaspiro- (4.4)nonane.

5. A compound of claim 1 which is 3,3,-dimethyl-8- (parachlorophenylalkylaminomethyl) 2,7-dioxaspiro- (4.4)nonane.

6. A compound of claim 1 which is 3,3,-dimethyl-8- (2bicyclo(2:2:1)-S-heptenyl-methylaminomethyl)-2,7- dioxaspiro(4.4)nonane.

7. A compound of claim 1 which is 3,3-dimethyl-8- (2bicyclo(2:2:1)-5-heptenylmethylaminomethyl)-2,7- diox aspiro 4.4) nonanehydrochloride.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

1. A COMPOUND OF THE FORMULA: